This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that integrates signals from integrin and growth factor receptors. Upon cell adhesion FAK is recruited to focal adhesions and activated. FAK activation involves a sequential mechanism of autophosphorylation, Src recruitment and Src phosphorylation of the activation loop of FAK. We have recently solved the crystal structure of autoinhibited FAK, which reveals a compact conformation where the N-terminal FERM domain binds and inhibits the kinase domain. We are now studying the mechanism of FAK activation. We have evidence that activated FAK adopts an extended and most likely flexible conformation. Hence, we have failed to obtain crystals of active forms of FAK. We therefore believe that Small Angle X-ray Scattering (SAXS) is the ideal technique to study FAK activation. During this cycle we have collected SAXS data of autoinhibited and mutationally activated forms of FAK. These experiments were conducted very recently and data analysis is not complete at this point. However, initial analysis suggests that SAXS will be able to provide low-resolution molecular envelopes that allow docking of high-resolution crystal structures of the individual domains. We therefore expect that further analysis and further experiments will give valuable insight into conformational changes that FAK undergoes upon activation.